The invention relates to the field of treatment and prevention of disease.
Oral ulcerative mucositis is a common, painful, dose-limiting side effect of drug and radiation therapy for cancer. The disorder is characterized by breakdown of the oral mucosa, which results in the formation of ulcerative lesions. The lesions that result cause inflammatory and ulcerative changes that result in pain and loss of function. Consequently, patients with mucositis often require an alteration in their diets and medication to manage pain. In addition, the presence of mucositis also influences other health and economic outcomes such as medication use, febrile days, use of total parenteral nutrition, length of hospital stay, and total hospital charges. The risk of mucositis often influences the choice of drug and dose to be used in the treatment of a patient and may preclude what is considered to be the optimum anti-cancer regimen. Patients who receive myeloablative therapy are at risk for local and systemic infection. Since the mouth is rich in indigenous microbiota, the loss of mucosal integrity associated with mucositis provides a portal of entry for invading bacteria at a time when a patient's resistance to infection is highly compromised because of chemotherapy-induced neutropenia. In fact, the mouth is the most frequently identified site of origin of systemic infection among granulocytopenic cancer patients.
Mucositis occurs to some degree in more than one third of all patients receiving anti-neoplastic drug therapy. The frequency and severity are significantly greater among patients who are treated with induction therapy for leukemia or with many of the conditioning regimens for bone marrow transplant. Among these individuals, moderate to severe mucositis (ulceration) is common in more than three-quarters of patients.
Patients who receive radiation therapy for tumors of the head and neck are also at high risk for oral mucositis. The frequency and severity of mucosal injury is a function of the total amount of radiation, the schedule of radiation delivery, and the concomitant use of chemotherapy. Increasing the rate of radiation exposure results in a higher incidence of mucositis. While the increasing trend of adding chemotherapy to the radiation regimen results in an improved tumor outcome, many of these protocols are highly stomatotoxic. Mucositis is often of such severity as to necessitate a break in treatment to allow the oral tissues to recover. Such interruptions reduce the overall effectiveness of therapy.
Clinically mucositis progresses through four stages:                1. An initial stage which is characterized by inflammatory changes of erythema and edema. Localized islands of hyperkeratosis may also been seen. This stage is symptomatically mild and may be successfully palliated by topical anesthetics.        2. Subsequently the mucosa breaks down and becomes eroded and atrophic with increasingly significant inflammatory changes. This stage is increasingly painful and may require systemic analgesic therapy in the form of NSAIDs or oral narcotics for adequate palliation.        3. The third stage of mucositis is the most symptomatic. Full thickness ulcers of the mucosa cause severe discomfort necessitating parenteral narcotic therapy. In addition, in the myelosuppressive patient, these ulcerations provide a systemic portal of entry for the oral microflora often leading to bacteremia and sepsis. Antimicrobial intervention is then required.        4. Finally, spontaneous healing occurs about 2-3 weeks after cessation of anti-neoplastic therapy.        
Historically mucositis was viewed as a process that was the sole result of epithelial damage. It was believed that the non-specific toxic effects of chemotherapy or radiation caused DNA damage to the rapidly dividing cells of the mucosal basal epithelium. This resulted in cell death, atrophic changes in the mucosa, and ulceration. However, four lines of observation suggested a biologic complexity that extended beyond an epithelial etiology. First, electron microscopic studies demonstrated damage to the endothelium and connective tissue that significantly preceded epithelial breakdown. Second, peripheral blood levels of pro-inflammatory cytokines increased proportionately when non-hematologic toxicities were observed. Third, attenuation of pro-inflammatory cytokine production and expression resulted in the amelioration of experimental mucositis. And fourth, alteration of the local environment by reducing its bacterial load and maintaining salivary function reduced the severity of mucositis.
The condition appears to represent a sequential interaction of oral mucosal cells and tissues including connective tissue, endothelium, epithelium, and inflammatory cells, pro-inflammatory cytokines, and local environmental factors such as bacteria and saliva. Damage to epithelial and connective tissue induces the release of inflammatory cytokines leading to mucosal damage. Additionally, both direct and indirect effects on epithelial cells result in either apoptotic or necrotic changes of basal epithelial cells; differentiation into new epithelial cells is halted. The arrest of epithelial cell renewal leads to atrophy followed by ulceration.
The findings appear to represent ‘downstream’ events, which result as a consequence of activation of at least two primary pathways: the transcription factor NF-κB and the ceramide pathway. It appears that reactive oxygen species (free radicals) generated by either chemotherapy or radiation are capable of initiating activation of both of these pivotal pathways in leading to mucositis.
Standard therapy for mucositis is predominantly palliative, including application of topical analgesics such as lidocaine and/or systemic administration of narcotics and antibiotics. Currently, there is no approved treatment for mucositis. There is, thus, a need for a method for treating and preventing mucositis.